The antibacterial drug nitrofurantoin (NF) has previously been shown to undergo one electron reduction in pulmonary microsomes with the subsequent production of oxygen metabolites and peroxidation of membrane lipids. A number of studies have attempted to relate the pulmonary toxicity of NF to the in vivo generation of toxic oxygen metabolites. Animals depleted of vitamin E have been shown to be markedly more susceptible to NF-induced lung damage than control animals. Other work has suggested that vitamin E represents an important antioxidant in the lungs and may be critical in protecting the organ against oxygen-mediated peroxidation of cellular unsaturated lipids. These results lend support to a role of toxic oxygen metabolites in NF pulmonary toxicity. Because vitamin E deficiency caused such a striking increase in the toxicity of NF, a study was undertaken to examine the pharmacokinetics of the drug in control and vitamin E deficient rats. Nitrofurantoin was rapidly absorbed following subcutaneous injection and was cleared from all tissues examined (blood, lung, liver and kidney) in a biphasic manner. Significant metabolism of the drug was observed and the disposition of NF metabolites was qualitatively similar to that of the parent compound. The most apparent difference between control and vitamin E deficient animals was a significant increase in tissue metabolite levels 4 to 16 hr post treatment. Unchanged NF was also elevated in all tissues examined by 16 hr in the vitamin E deficient animals. Urinary excretion of NF and metabolites over 16 hr accounted for 68% and 35% of the total dose in control and vitamin E deficient rats. The present study illustrates a marked alteration in NF disposition in animals fed a diet lacking vitamin E, compared to control animals. The observed alterations appear to be related to a decreased renal clearance of both NF and metabolites. These data provide an alternative explanation for the previously observed enhanced pulmonary toxicity of NF in vitamin E deficient animals.